This web page was produced as an assignment for Genetics 564, an undergraduate course at UW-Madison.
So what is impulsivity, really?____________________________________________________________________________
Some urges that may be classified as “impulsive” range from binge-watching TV and blurting out awful words you’ll regret later, to pathological gambling and substance abuse.
Some urges that may be classified as “impulsive” range from binge-watching TV and blurting out awful words you’ll regret later, to pathological gambling and substance abuse.
But like many other behavioural traits, there really is no precise way to define impulsivity: It is considered to be multifactorial, with many varieties proposed by researchers who have worked with human subjects. Some of the said proposed varieties include lack of persistence, inattention and reward dependence; not all of which may be agreed upon by different researchers [1].
A study notes that impulsivity and the tendency to procrastinate may be genetically linked: Based on questionnaire responses by twins, they found that procrastination and impulsivity had a phenotypic correlation of 0.65. The paper also notes that both traits share one characteristic, that is, the imprecise timing when it comes to the execution of an action: Procrastination involves the delaying of an action, while impulsivity involves ‘giving in to temptation’; both of which affect progress on long-term goals. This is in line with the postulation that impulsivity is a multifactorial construct.
Generally, however, impulsivity is characterized by the tendency to act with little forethought and ‘rapid, unplanned reactions towards internal and external stimuli’ [2]. Rash impulsiveness has also been associated with clinical psychiatric disorders such as ADHD, mania and substance dependence [3].
Dopamine receptors, dopamine and the DRD2 gene__________________________________________________________
The DRD2 gene encodes the dopamine receptor D2 (DRD2) [4]. DRD2 is one of five known dopamine receptors [5], which are a class of G-protein coupled receptors (GPCRs). And as its name implies, the signalling molecule dopamine is the primary ligand that interacts with DRD2. Dopamine plays various roles in human physiology and has a major role as a brain neurotransmitter. In the central nervous system (CNS), it regulates various functions including locomotor activity, emotional responses and neuroendocrine secretion. Dysregulation of the dopamine system was found to be linked to neurodegenerative diseases like Parkinson’s disease, and is also thought to contribute to psychiatric disorders [6].
A study notes that impulsivity and the tendency to procrastinate may be genetically linked: Based on questionnaire responses by twins, they found that procrastination and impulsivity had a phenotypic correlation of 0.65. The paper also notes that both traits share one characteristic, that is, the imprecise timing when it comes to the execution of an action: Procrastination involves the delaying of an action, while impulsivity involves ‘giving in to temptation’; both of which affect progress on long-term goals. This is in line with the postulation that impulsivity is a multifactorial construct.
Generally, however, impulsivity is characterized by the tendency to act with little forethought and ‘rapid, unplanned reactions towards internal and external stimuli’ [2]. Rash impulsiveness has also been associated with clinical psychiatric disorders such as ADHD, mania and substance dependence [3].
Dopamine receptors, dopamine and the DRD2 gene__________________________________________________________
The DRD2 gene encodes the dopamine receptor D2 (DRD2) [4]. DRD2 is one of five known dopamine receptors [5], which are a class of G-protein coupled receptors (GPCRs). And as its name implies, the signalling molecule dopamine is the primary ligand that interacts with DRD2. Dopamine plays various roles in human physiology and has a major role as a brain neurotransmitter. In the central nervous system (CNS), it regulates various functions including locomotor activity, emotional responses and neuroendocrine secretion. Dysregulation of the dopamine system was found to be linked to neurodegenerative diseases like Parkinson’s disease, and is also thought to contribute to psychiatric disorders [6].
Image source [18]: De Mei et al., 2009
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The image to the left is a simplified illustratration of dopamine synthesis and signalling at neuronal synapses. Circled in green are representations of DRD2 proteins. At presynaptic sites, phosphorylation activates tyrosine hydroxylase (TH), which converts the amino acid tyrosine to L-DOPA. L-DOPA is a precursor to dopamine (DA), which is released into the synaptic cleft. DRD2 regulates dopamine synthesis and release at the presyanaptic sites. DA acts as a ligand for DRD2 at postsynaptic sites, which results in the regulation of GPCR signal transduction. |
The cytogenetic location of the human DRD2 gene is 11q23. That is, on the long arm of chromosome 11 at position 23 [7].
But what is the link between DRD2 impulsivity?____________________________________________________________
Studies in animal models have shown that low DRD2 availability is inversely related to impulsivity: Mutant mice lacking D2-like receptors display high rates of cocaine self-administration, and similar results have also been demonstrated in rhesus monkeys with low DRD2 availability [8].
In humans, DRD2 is said to be associated with impulsivity-related behaviour like drug addiction and smoking [10]. Low DRD2 levels in the striatum of the forebrain have also been reported in morbidly obese subjects: It was suggested that low DRD2 levels contribute to overeating due to modulation of the striatal prefrontal pathways, which participate in inhibitory control [11]. In addition, various polymorphisms in the DRD2 gene have been suggested to influence the severity of impulsivity-related behavior and antipsychotic treatment effectiveness [17]. Some other studies suggesting a link between DRD2 polymorphisms and impulsivity include the following:
However, it should be noted that there are also several studies countering claims of associations between DRD2 and impulsive behaviour in humans [12,13,14]. A clear link between DRD2 and impulsive behaviour is therefore debateable.
Nevertheless, neural and molecular mechanisms related to the onset of impulsive behavior have not been extensively characterized. Due to the major role of dopamine in the CNS, it would likely be useful to study dopamine receptors like DRD2 in order to decipher pathways related to psychiatric disorders and also neurodegenerative diseases, for which impulsivity is often found as a symptom in [15,16].
Studies in animal models have shown that low DRD2 availability is inversely related to impulsivity: Mutant mice lacking D2-like receptors display high rates of cocaine self-administration, and similar results have also been demonstrated in rhesus monkeys with low DRD2 availability [8].
In humans, DRD2 is said to be associated with impulsivity-related behaviour like drug addiction and smoking [10]. Low DRD2 levels in the striatum of the forebrain have also been reported in morbidly obese subjects: It was suggested that low DRD2 levels contribute to overeating due to modulation of the striatal prefrontal pathways, which participate in inhibitory control [11]. In addition, various polymorphisms in the DRD2 gene have been suggested to influence the severity of impulsivity-related behavior and antipsychotic treatment effectiveness [17]. Some other studies suggesting a link between DRD2 polymorphisms and impulsivity include the following:
- There is a significantly higher number of opium users compared to non-opium users possessed the DRD2 A1 allele [9].
- 48.7% of non-Hispanic Caucasians who smoked at least one pack a day and were not able to successfully quit smoking carried the DRD2 A2 allele. This percentage is significantly higher than that in study controls [10].
- The A allele of the DRD2 single nucleotide polymorphism (SNP) rs1076560 was found to be more prevalent in alcoholic patients compared to a control group [19].
- The prevalence of the A1 allele was significantly increased in patients with Tourette's syndrome, ADHD, and alcoholism [20].
- There may be an association between the DRD2 Fokl-1 allele and the onset and intensity of smoking [21].
- A promoter polymorphism and exon 7 SNPs in DRD2 were significantly associated with diagnosis of anorexia nervosa [22].
However, it should be noted that there are also several studies countering claims of associations between DRD2 and impulsive behaviour in humans [12,13,14]. A clear link between DRD2 and impulsive behaviour is therefore debateable.
Nevertheless, neural and molecular mechanisms related to the onset of impulsive behavior have not been extensively characterized. Due to the major role of dopamine in the CNS, it would likely be useful to study dopamine receptors like DRD2 in order to decipher pathways related to psychiatric disorders and also neurodegenerative diseases, for which impulsivity is often found as a symptom in [15,16].
References
(1) Evenden, J. L. (1999). Varieties of impulsivity. Psychopharmacology, 146(4), 348-361.
(2) http://www.impulsivity.org
(3) Dalley, J. W., & Roiser, J. P. (2012). Dopamine, serotonin and impulsivity.Neuroscience, 215, 42-58
(4) http://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=1813
(5) Contreras, F., et al. (2002). Dopamine, hypertension and obesity. In International Congress Series (Vol. 1237, pp. 99-107). Elsevier.
(6) Jaber, M., et al. (1996). Dopamine receptors and brain function. Neuropharmacology, 35(11), 1503-1519.
(7) http://ghr.nlm.nih.gov/gene/DRD2
(8) Dalley, J. W., et al. (2007). Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. science, 315(5816), 1267-1270.
(9) Najafabadi, M. S., et al. (2005). Association between the DRD2 A1 allele and opium addiction in the Iranian population. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 134(1), 39-41.
(10) Comings, D. E., et al. (1996). The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking. Pharmacogenetics and Genomics, 6(1), 73-79.
(11) Volkow, N. D., et al. (2008). Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors.Neuroimage, 42(4), 1537-1543.
(12) Gelernter, J., et al. (1991). No association between an allele at the D2 dopamine receptor gene (DRD2) and alcoholism. Jama, 266(13), 1801-1807.
(13) Gorwood, P., et al. (2000). Reappraisal of the association between the DRD2 gene, alcoholism and addiction. European Psychiatry, 15(2), 90-96.
(14) Lee, J. F., et al. (1999). No association between DRD2 locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population.Alcoholism: Clinical and Experimental Research, 23(4), 592-599.
(15) Antonelli, F., Ray, N., & Strafella, A. P. (2011). Impulsivity and Parkinson's disease: More than just disinhibition. Journal of the neurological sciences,310(1), 202-207.
(16) Prado-Lima, P. A. S. D. (2009). Pharmacological treatment of impulsivity and aggressive behavior. Revista Brasileira de Psiquiatria, 31, S58-S65.
(17) Zahari, Z., Teh, L. K., Ismail, R., & Razali, S. M. (2011). Influence of DRD2 polymorphisms on the clinical outcomes of patients with schizophrenia. Psychiatric genetics, 21(4), 183-189.
(18) De Mei, C., Ramos, M., Iitaka, C., & Borrelli, E. (2009). Getting specialized: presynaptic and postsynaptic dopamine D2 receptors. Current opinion in pharmacology, 9(1), 53-58.
(19) Sasabe, T., Furukawa, A., Matsusita, S., Higuchi, S., & Ishiura, S. (2007). Association analysis of the dopamine receptor D2 (DRD2) SNP rs1076560 in alcoholic patients. Neuroscience letters, 412(2), 139-142.
(20) Comings, D. E., Comings, B. G., Muhleman, D., Dietz, G., et al. (1991). The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. Jama, 266(13), 1793-1800.
(21) Comings, D. E., Ferry, L., Bradshaw-Robinson, S., Burchette, R., et al. (1996). The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking. Pharmacogenetics and Genomics, 6(1), 73-79.
(22) Bergen, A. W. et al. (2005). Association of multiple DRD2 polymorphisms with anorexia nervosa. Neuropsychopharmacology, 30(9), 1703-1710.
(1) Evenden, J. L. (1999). Varieties of impulsivity. Psychopharmacology, 146(4), 348-361.
(2) http://www.impulsivity.org
(3) Dalley, J. W., & Roiser, J. P. (2012). Dopamine, serotonin and impulsivity.Neuroscience, 215, 42-58
(4) http://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=1813
(5) Contreras, F., et al. (2002). Dopamine, hypertension and obesity. In International Congress Series (Vol. 1237, pp. 99-107). Elsevier.
(6) Jaber, M., et al. (1996). Dopamine receptors and brain function. Neuropharmacology, 35(11), 1503-1519.
(7) http://ghr.nlm.nih.gov/gene/DRD2
(8) Dalley, J. W., et al. (2007). Nucleus accumbens D2/3 receptors predict trait impulsivity and cocaine reinforcement. science, 315(5816), 1267-1270.
(9) Najafabadi, M. S., et al. (2005). Association between the DRD2 A1 allele and opium addiction in the Iranian population. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 134(1), 39-41.
(10) Comings, D. E., et al. (1996). The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking. Pharmacogenetics and Genomics, 6(1), 73-79.
(11) Volkow, N. D., et al. (2008). Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors.Neuroimage, 42(4), 1537-1543.
(12) Gelernter, J., et al. (1991). No association between an allele at the D2 dopamine receptor gene (DRD2) and alcoholism. Jama, 266(13), 1801-1807.
(13) Gorwood, P., et al. (2000). Reappraisal of the association between the DRD2 gene, alcoholism and addiction. European Psychiatry, 15(2), 90-96.
(14) Lee, J. F., et al. (1999). No association between DRD2 locus and alcoholism after controlling the ADH and ALDH genotypes in Chinese Han population.Alcoholism: Clinical and Experimental Research, 23(4), 592-599.
(15) Antonelli, F., Ray, N., & Strafella, A. P. (2011). Impulsivity and Parkinson's disease: More than just disinhibition. Journal of the neurological sciences,310(1), 202-207.
(16) Prado-Lima, P. A. S. D. (2009). Pharmacological treatment of impulsivity and aggressive behavior. Revista Brasileira de Psiquiatria, 31, S58-S65.
(17) Zahari, Z., Teh, L. K., Ismail, R., & Razali, S. M. (2011). Influence of DRD2 polymorphisms on the clinical outcomes of patients with schizophrenia. Psychiatric genetics, 21(4), 183-189.
(18) De Mei, C., Ramos, M., Iitaka, C., & Borrelli, E. (2009). Getting specialized: presynaptic and postsynaptic dopamine D2 receptors. Current opinion in pharmacology, 9(1), 53-58.
(19) Sasabe, T., Furukawa, A., Matsusita, S., Higuchi, S., & Ishiura, S. (2007). Association analysis of the dopamine receptor D2 (DRD2) SNP rs1076560 in alcoholic patients. Neuroscience letters, 412(2), 139-142.
(20) Comings, D. E., Comings, B. G., Muhleman, D., Dietz, G., et al. (1991). The dopamine D2 receptor locus as a modifying gene in neuropsychiatric disorders. Jama, 266(13), 1793-1800.
(21) Comings, D. E., Ferry, L., Bradshaw-Robinson, S., Burchette, R., et al. (1996). The dopamine D2 receptor (DRD2) gene: a genetic risk factor in smoking. Pharmacogenetics and Genomics, 6(1), 73-79.
(22) Bergen, A. W. et al. (2005). Association of multiple DRD2 polymorphisms with anorexia nervosa. Neuropsychopharmacology, 30(9), 1703-1710.